tbuckley/cabot-search huggingface dataset:
Outcomes in premenopausal patients with HR+/HER2- breast cancer and lymph node micro-metastasis based on the 21-gene recurrence score.
Authors: Nadeem Bilani, Rima Patel, Amy Tiersten
Journal: Journal of Clinical Oncology (2023)

571 Background: Postmenopausal patients with hormone receptor positive, HER2-negative (HR+/HER2-) early breast cancer (EBC) and 21-gene OncotypeDX (ODX) recurrence scores (RS) &lt;26 do not benefit from chemoendocrine therapy (‘CET’) compared to endocrine monotherapy (‘E’). The TAILORx and RxPONDER trials demonstrated this was consistent in node-negative and node-positive disease, respectively. In premenopausal patients, however, guidelines for those with low RS diverge between disease involving 0 (pN0) vs. 1-3 (pN1a-c) lymph nodes. Additionally, treatment decisions are less clear for patients with micro-metastasis (pN1mi), who comprised only about 10% of patients in RxPONDER. This study used the National Cancer Database (NCDB) to assess treatment patterns and survival outcomes in premenopausal patients with EBC and lymph node micro-metastasis. Methods: A cohort of patients aged &lt;50, diagnosed between 2004-2019 with HR+/HER2- EBC and who underwent ODX testing, was recruited from the NCDB. (A) Firstly, we described demographic and clinical characteristics of a sub-cohort with micro-metastasis using univariate statistics. (B) We confirmed the prognostic value of ODX in this sub-cohort with multivariate Cox regression analysis of overall survival (OS). (C) We explored patterns of practice amongst the total cohort with ODX &lt;26 with chi-squared testing for differences in CET use by nodal status. (D) To elucidate the predictive value of this assay, we performed Kaplan-Meier models comparing OS for those with RS &lt;26 receiving E vs. CET, controlling granularly for nodal status: (i) pN1a-c, (ii) pN1mi, and (iii) pN0. Results: Of n=72,068 patients aged &lt;50 with HR+/HER2- EBC and ODX data, 6.1% (n=4,402) had micro-metastasis. (A) The median age of this subgroup was 45 (IQR 41-47) years. Most tumors were grade II (n=2,472, 57.7%) with ductal histology (n=3,500, 80.3%). 73.4% of pN1mi cases had RS &lt;26, while 26.6% had RS ≥26. (B) Multivariate Cox regression – adjusting for comorbidity, race and chemotherapy use – confirmed significance in this pN1mi cohort of RS ≥26 prognosticating poorer OS compared to RS 0-15 (HR 4.42, 95% CI 2.35-8.31, p&lt;0.001). (C) 29.0% (n=1,033) of patients with pN1mi and ODX &lt;26 underwent CET, greater than 15.2% (n=6,568) with pN0 and less than 47.3% (n=2,884) with pN1a-c staging (p&lt;0.001). (D) A benefit in OS (p=0.017) was observed in cases with RS&lt;26 and pN1a-c using CET (5-year OS: 99%) vs. E (5-year OS: 97.5%), but not in pN1mi (p=0.49) or pN0 (p=0.57) disease. Conclusions: The management of premenopausal patients with HR+/HER2- EBC, isolated micro-metastasis, and ODX &lt;26 is unclear. Our large registry study found the addition of chemotherapy to endocrine therapy was associated with improved survival in cases with ODX&lt;26 involving 1-3 lymph nodes, but not in node-negative or micro-metastatic disease. Prospective trials are needed to confirm these findings.
Evaluation of PAM50 intrinsic subtypes and risk of recurrence (ROR) scores in premenopausal women with early-stage HR+ breast cancer: A secondary analysis of the SOFT trial.
Authors: Lauren Claire Brown, Stephen James Luen, Ramyar Molania, Franco Caramia, Peter Savas, Courtney VanGeelen, Nuria Chic, Gini F. Fleming, Rosita Kammler, Marco Colleoni, Giuseppe Viale, Terence Paul Speed, Meredith M. Regan, Prudence A. Francis, Sherene Loi
Journal: Journal of Clinical Oncology (2023)

504 Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS. The purpose of this study is to assess the prognostic and predictive ability of PAM50 intrinsic subtypes and ROR scores in premenopausal women with HR+/HER2- breast cancer in the SOFT trial. Methods: Gene expression analyses were performed via the NanoString Breast Cancer 360 assay on RNA isolated from FFPE tumor samples from the SOFT trial that were HR+/HER2- (n=1245/3047). PAM50 subtype and ROR score were determined centrally by NanoString Technologies (Seattle, WA, USA), blinded to clinical characteristics, treatment and outcome. Median follow-up was 12 years. Primary endpoint in this study was distant recurrence-free interval (DRFI). Secondary endpoints were breast cancer-free interval (BCFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of PAM50 intrinsic subtypes and ROR categories (low vs intermediate vs high), and secondarily ROR score as a continuous variable. We also investigated differences between very young (&lt;40yrs) vs young (&gt;40yrs) women. Results: Tumor samples from 1084/1245 (87%) patients successfully completed PAM50 testing and are included in this analysis. Patient characteristics in this cohort were similar to the entire SOFT trial population. Intrinsic subtype and ROR category distribution is described below. Subtype distribution significantly differed between very young vs young premenopausal women, with fewer luminal A and more luminal B and non-luminal tumors seen in the very young (p&lt;0.001). The ROR score distribution also differed significantly: in node-negative patients there were significantly more ROR-high scores amongst very young compared to young women (36% vs 14%, p&lt;0.001). Conclusion: Breast cancer diagnosed in very young women has aggressive disease biology. Prognostic and predictive analyses of both intrinsic subtypes and the ROR score are ongoing and will be presented at the meeting. Clinical trial information: NCT00066690 . [Table: see text]
Negative estrogen receptor expression assessed by 18F-FES PET in metastatic breast cancer with ER-positive primary tumor.
Authors: Biyun Wang, Shuhui You, Yizhao Xie, Mengjing Ji, Zhongyi Yang
Journal: Journal of Clinical Oncology (2023)

1034 Background: The 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) technique provides a convenient method to evaluate the overall estrogen receptor (ER) expression in metastatic breast cancer (MBC) patients. There are long debates on the characteristics and treatment strategy of patients with positive primary ER lesion but negative ER expression in metastatic disease. 18F-FES PET offers an opportunity to answer this question. Methods: This study enrolled MBC patients with ER-positive primary tumor who received 18F-FES PET/CT in our center. Descriptive statistics were used in clinicopathologic characteristics and compared with Chi square test or t test. Progression‐free survival (PFS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: 16.46% (52/314) patients with an ER-positive primary tumor had negative ER expression assessed by 18F-FES for MBC prior to receiving first-line systemic therapy. The rate of ER-negativity tested by 18F-FES was negatively co-related with levels of ER expression in early stage, with a positive to negative conversion in 2 of 3 (46.3%) ER-low (ie, ER 1%-9%) tumors, 7 of 10 (70.0%) ER-moderate (ie, ER 10%-49%) tumors, 16 of 114 (14.0%) ER-high (ie, ER 50%-95%) tumors, and 1 of 8 (12.5%) ER-very high (ie, ER &gt; 95%) tumors (p &lt; 0.001). Chemotherapy (83.33%, 40/48) was the most common treatment strategy afterward, among which capecitabine monotherapy (64.29%, 27/42) was a dominant alternative. PFS was significantly prolonged with capecitabine alone versus other chemotherapy (median PFS: 13.14 vs 6.21 months, p = 0.035). Conclusions: 18F-FES could identify negative conversion of ER in MBC which occurred frequently. Patients with lower ER expression in the primary lesion were more likely to have negative ER expression in the metastasis. In real-world clinical practice, chemotherapy was the primary choice by most physicians and capecitabine monotherapy had shown good efficacy.
Relation between circulating biomarkers at diagnosis of early luminal-like breast cancer and subsequent risk of distant metastases.
Authors: Yentl Lambrechts, Abhishek Garg, Giuseppe Floris, Kevin Punie, Patrick Neven, Ines Nevelsteen, Jannes Govaerts, François Richard, Annouschka Laenen, Christine Desmedt, Hans Wildiers, Sigrid Hatse
Journal: Journal of Clinical Oncology (2023)

1077 Background: Predicting development of distant metastases after treatment of early luminal breast cancer (BC) remains a major challenge. Besides clinical-pathological features of the primary tumor, baseline circulating factors could also play a role as prognostic biomarkers. Methods: Patients with newly diagnosed early BC (grade 2/3, ER+, HER2-non- amplified) were selected from our institutional BC registry, with associated blood biobank collecting baseline plasma/serum samples at diagnosis. Circulating biomarkers potentially modulating the metastatic process (chemokines, micro-RNAs (miRNAs), Leukemia Inhibitory Factor (LIF), and osteopontin), and serum-induced functional myeloid interferon (IFN)) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling-responses, were measured at early BC diagnosis (before any treatment) in patients who subsequently developed distant metastasis within five years after diagnosis and therapy (META group) and in a 1:1 control group of patients, pairwise matched for age, tumor grade, stage, and histological subtype, who remained disease-free for at least seven years (NON-META group). All blood biomarkers were analyzed pair-wisely using the univariable Wilcoxon signed rank test (two-tailed). Multiple testing correction was done by applying a false discovery rate (FDR) of 0.05. In addition, a multivariable logistic regression analysis (MVA) was performed to find blood biomarkers signatures that can predict the development of metastases at first diagnosis of early BC. Results: 102 matched patient pairs were included. Univariable paired analysis showed significantly increased baseline expression of LIF (p=0.012) and six miRNAs (miR-143-3p: p=0.015; miR-197-3: p:&lt;0.001; miR-223-3p: p=0.006; miR-223-5p: p=0.045; miR-338-3p: p=0.045; miR-365a-3p: p=0.025), and decreased serum-induced myeloid -IFN-responses (p=0.023) and ten miRNAs (let-7b-5p: p=0.006; miR-106a-5p: p=0.045; miR-106b-5p: p=0.015; miR-107: p=0.014; miR-144-3p: p=0.015; miR-15a-5p: p=0.045; miR-15b-3p: p=0.032; miR-185-5p: p=0.045; miR-18a-5p: p=0.015; miR-30b-5p: p=0.045) in the META group compared to the NON-META group. MVA yielded a seven-biomarker signature, which includes miR-197-3p (p=0.008), miR-139-5p (p&lt;0.001), LIF (p=0.007), miR-106b-5p (p=0.003), serum-induced IFN/ISG response (p=0.006), miR-652-3p (p=0.015), and miR-133b (p=0.025) with a C-index of 0.79 (0.70-0.88) to predict distant metastases. After 5-fold internal cross-validation, C-index was 0.63 (0.52-0.74). Conclusions: Baseline circulating miRNAs, LIF, and serum-induced IFN-response levels at early luminal BC diagnosis are associated with subsequent distant metastases. Further external validation is required to confirm the prognostic value of these biomarkers.
Differential genomic and transcriptomic analysis of invasive lobular and ductal carcinomas.
Authors: Jason A Mouabbi, Funda Meric-Bernstam, Svetlana Khorkova, Polina Turova, Nikita Kotlov, Konstantin Chernyshov, Vladimir Kushnarev, Anna Love, Patrick Clayton, Krystle Nomie, Nathan Fowler, Debu Tripathy
Journal: Journal of Clinical Oncology (2023)

579 Background: Invasive lobular carcinoma (ILC) is more aggressive than hormone receptor (HR)-positive invasive ductal carcinoma (IDC). However, in practice, ILC and IDC are often treated in a similar fashion with endocrine therapy and chemotherapy. Identifying novel biomarkers, genetic alterations, transcriptomic features, and tumor microenvironment (TME) variations could initiate the development of personalized treatment plans for patients with ILC. Methods: We collected ILC and luminal (non-basal/non-HER2) IDC samples from four datasets (TCGA, METABRIC, RATHER PMC4700448, and UQCCR PMC31263747) and performed differential expression and gene set enrichment analyses, revealing novel genomic, transcriptomic, and TME differences. Using methods from Bagaev et al., we quantified the activity of 29 functional gene expression signatures with single sample gene set enrichment analysis before clustering the samples into five TME subtypes; statistical significance was measured with the Mann-Whitney U test. Differential expression analysis of RNA-Seq data was completed using DESeq2. Further, we analyzed the frequency of specific biomarkers to identify potential therapeutic options. Mutations and biomarker enrichment were assessed using the chi-squared test. Results: We analyzed 1,735 samples (1,442 luminal IDCs and 293 ILCs). CDH1 mutations were more prevalent in ILC samples (56%) compared to IDC samples (6%). Of the 44% of ILC samples with wild-type CDH1, 90% had low CDH1 expression. Inference models showed differences in transcription factors expression between ILC and IDC. ILC had significantly higher expression of TFAP2B, SOCS2, NOSTRIN, THBS4, SCUBE2, and GDF9 and lower expression of CDCA4, PSMG1, LMOD1, and SLC7A5 (adj p &lt; 0.0001 for all genes). Analysis of the TME showed that 44% of ILC samples were immune enriched with high PDL1, CTLA4, and LAG3 expression. In comparison, approximately 30% of ILC samples contained enhanced vascularization and expressed high VEGFA, PDGFRA, and PDGFRB. Finally, compared to luminal IDC, ILC tend to have a statistically significant higher TROP2 expression, similar to that seen in basal subtype. Conclusions: ILC and IDC expressed distinct genomic alterations, gene expression, transcriptomic features, TMEs, and biomarkers. These differences can be used as a blueprint to tailor ILC phenotype-specific interventional clinical trials.
Pathologic complete response in germline mutation carriers by mutation type and biomarkers in a safety-net population.
Authors: Sidrah Shah, Shaun Bulsara, Susan G. Hilsenbeck, Cathy Sullivan, Georgiann Garza, Tiffaney Tran, Ria Brown, Mary Fang, C. Kent Osborne, Mothaffar F. Rimawi, Nicole Higashiyama, Julie R. Nangia
Journal: Journal of Clinical Oncology (2023)

e12628 Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy in early to locally advanced breast cancer has important prognostic implications with high cure rates. Understanding its associations with hereditary breast cancer mutations, specifically by mutation type and biomarkers, adds additional prognostic value. In this retrospective chart review, we investigated pCR rates among patients who have undergone genetic testing in a safety-net hospital comprised primarily of racial minorities. Methods: All patients at Smith Clinic (affiliated with the Harris County’s safety-net hospital system) with a diagnosis of stage I-III breast cancer who agreed to undergo genetic testing, were found to have a genetic mutation from October 1, 2009 to September 30, 2019, and received neoadjuvant chemotherapy followed by lumpectomy or mastectomy were included. Demographic and clinical characteristics as well as post-operative pathologic data were collected. Results: 71 patients qualified for the analysis. 50 (70%) were Hispanic, and the median age was 42. 41 (58%) were BRCA1+, 13 (18.3%) were BRCA2+, and 12 (16.9%) were PALB2+. They ranged from stage I-III, with 49% falling in stage III. In terms of biomarker status, triple negative breast cancer (TNBC) comprised 35 (49%) patients, HER2+ 8 (11%), and ER+ and/or PR+ (HER2-) 28 (39%). 36 (51%) were treated with both neoadjuvant anthracycline and taxanes. pCR rates were highest among triple negative cancers (17, 48%). 16 (39%) of patients with a BRCA1 mutation achieved pCR, 5 (38.5%) of BRCA2 patients and 3 (25%) of PALB2 patients. RCB class by mutation type and biomarker status will be reported as well as a more detailed analysis of pCR by mutation status and biomarkers. Conclusions: In our population of primarily Hispanic patients, those with BRCA1, BRCA2, and PALB2 had the highest pCR rates. As expected, patients with TNBC had the highest pCR rates. More data in patients with germline mutations may help us determine prognosis and how to best treat these patients. [Table: see text]
Cost-effectiveness of trastuzumab deruxtecan in HER2 low metastatic breast cancer.
Authors: James Dickerson, Marcus Moen, Perry Nielsen, Edward Tran, Wesley Suen, Jeremy D Goldhaber-Fiebert, Fernando Alarid-Escudero
Journal: Journal of Clinical Oncology (2023)

1593 Background: In recent years, metastatic breast cancer treatment has been revolutionized by new therapies that improve overall survival in phase three randomized clinical trials. These drugs are often more expensive than traditional cytotoxics. In 2022, the Destiny-Breast04 trial results showed that trastuzumab deruxtecan (T-DXd) improved survival in HER2 low metastatic breast cancer patients; FDA approval shortly thereafter greatly expanded the potential market capitalization of T-DXd. While the trial demonstrated T-DXd’s clinical efficacy, its cost-effectiveness remains unknown. Methods: We developed a decision-analytic state transition Markov model to simulate a hypothetical cohort of HER2 low metastatic breast cancer patients to assess the cost-effectiveness of T-DXd compared to a physician's choice chemotherapy from a US healthcare payer perspective over a lifetime horizon. Each month, simulated patients could remain progression-free, progress, have a non-interstitial lung disease (ILD) treatment-related adverse event leading to drug discontinuation (TRAE), have ILD leading to drug discontinuation, progress after either a TRAE or ILD, or die. Patients with either a TRAE or ILD were presumed to be progression free directly after discontinuation of the offending agent, and hence eligible for a different therapy. We calibrated the model to outcome data from the Destiny-Breast04 trial, supplemented with data from other relevant metastatic breast cancer clinical trials. Health-related quality-of-life weights were derived from studies of metastatic breast cancer patients. Drug prices (2020 USD) were extracted from the Federal Supply Schedule. Outcomes included discounted (3% annual) quality-adjusted life years (QALYs), life years, lifetime costs, and incremental cost-effectiveness ratios (ICER). We varied T-DXd price and efficacy in a two-way sensitivity analysis to assess our findings’ robustness. Results: Modeled life expectancies with T-DXd and chemotherapy were 26.5 and 21.5 months, respectively (T-DXd: 1.19 QALYs; chemotherapy: 0.93 QALYs). Discounted lifetime costs were 315,000 for T-DXd and 203,000 for chemotherapy; T-DXd cost 431,000 per QALY gained, surpassing a cost effectiveness threshold of 150,000 per QALY gained. The two-way sensitivity analysis showed that, across a range of plausible efficacies, T-DXd would need a price reduction of approximately 50% to be cost-effective at the $150,000 threshold. Conclusions: While providing clinical benefits, our model-based analysis finds that at current prices, T-DXd for HER2 low metastatic breast cancer is not cost-effective at traditional thresholds. Substantial price reduction for T-DXd to a level much closer to prices of comparator cytotoxics could greatly increase the value for money T-DXd provides patients.
Long-term oncologic outcomes after omitting axillary surgery in older women with early stage, node-negative breast cancer: A systematic review and meta-analysis.
Authors: Mariam Rana, Soyon Lee, Alistair Lindsay, Juan Carlos Silva Godinez, Erik Vakil, Evelyn Waugh
Journal: Journal of Clinical Oncology (2023)

525 Background: In 2016, Choosing Wisely recommended the omission of routine sentinel lymph node biopsy (SLNB) in early stage, clinically node-negative, hormone receptor-positive, Her2-negative breast cancer in women ≥70 years old, although data supporting this was limited. Our study aimed to examine the long-term impact of omitting axillary staging in elderly women undergoing surgery for early stage, clinically node-negative breast cancer. Methods: A systematic review and meta-analysis was conducted. Medline (Ovid) and Embase were searched for published papers and abstracts using a systematic search strategy. Randomized and observational studies comparing women aged ≥70 years of age with early-stage, clinically node-negative breast cancer undergoing surgery for breast cancer with and without axillary staging, were included. Included studies reported at least one of the following outcomes: axillary recurrence (primary outcome), disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival. Risk ratios (RR) were calculated as summary estimates for all outcomes. A weighted pooled mean difference and 95% CI was calculated using a random-effects inverse variance meta-analysis for each outcome. Heterogeneity was calculated using I 2 statistics, and explored using meta-regression. The Newcastle-Ottawa Scale was used to assess the methodological quality of eligible trials, based on the selection of patients, comparability of cohorts, and the methods of outcome assessment. Results: Nine studies were eligible for meta-analysis, including data for 48,523 patients. For the primary outcome of axillary recurrence, data for 3,591 patients was meta-analyzed. Axillary staging was found to reduce the risk of axillary recurrence compared to no axillary staging, although this was not statistically significant (RR 0.59, 95% CI: 0.26 to 1.35, I 2 = 46.6%, p = 0.21). For overall mortality, data for 14,981 patients was meta-analyzed, and a statistically significant protective effect of axillary staging on overall mortality was demonstrated (RR 0.55, 95% CI: 0.33 to 0.90, I 2 = 78.1%, p= 0.003). No significant differences were observed in DFS (RR 1.02, 95% CI: 0.51 to 2.07, I2 = 0.0%, p = 0.37) and BCSS (RR 0.96, 95% CI: 0.57 to 1.62, I2 = 0.0%, p = 0.78). Conclusions: Omission of axillary surgery to stage the axilla may be associated with a higher risk of overall mortality in older women with early-stage breast cancer compared to those who undergo axillary surgery. Omission of axillary surgery in this patient population should be carefully tailored to the individual patient, taking into consideration co-morbidity, life expectancy, and formal measures of frailty. Randomized trials are required to further explore the oncologic safety of omitting axillary staging in women aged 70 years or older undergoing breast cancer surgery.